A solid dispersion is a molecular dispersion of a compound, particularly a drug substance, within a lipidic carrier matrix. Formation of a molecular dispersion (solid solutions) of such a compound provides a means of reducing the particle size of the compound to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the compound is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles. The use of solid dispersion compositions of sparingly soluble compounds has been used to enhance the solubility, dissolution and bioavailability of the sparingly water-soluble compound.
Conventional techniques for producing solid dispersions include melt processing, wherein the compound and a carrier are heated to a temperature above the melting point of both the carrier and compound, which results in the formation of a fine colloidal (as opposed to molecular) dispersion of compound particles, with some solubilization of the compound in the carrier matrix. Processing of such a molten mixture often includes rapid cooling, which results in the formation of a congealed mass which must be subsequently milled to produce a powder which can be filled into capsules or made into tablets. This melt processing technique has several disadvantages. For example, if the compound and carrier are not miscible in the molten state, non-homogeneous mixtures may be formed. In addition, the process is also limited for use with compounds and carriers that do not decompose at high temperatures required to melt the components.
When difficulty arises with thermal instability and/or miscibility between the compound and the carrier, a hybrid method for making solid dispersions, called the fusion-solvent method may be used. In this technique, the compound substance is first dissolved in a small quantity of organic solvent and then added to a molten carrier. The solvent is then evaporated to generate a product that can be subsequently milled to produce a powder. This solvent process also has disadvantages, for example, explosion hazard during production, difficulty in removing all traces of solvent from the solid dispersion product for pharmaceutical use, diffusion of solvent into the atmosphere causing pollution and the potential for compound recrystallization following solvent removal.
Stability of these conventional formulations can be problematic. The use of high heat or the use of organic solvents may be required to solubilize the compound into the carrier matrix. After removal of these solubilization factors (i.e., after cooling or removal of the solvent), the compound may no longer be soluble in the carrier. In the most problematic cases, recrystallization of the compound in the dispersion matrix may occur, leading to significant reduction in the dissolution and bioavailability of the compound.
Post-processing of these conventional formulations to prepare the final physical form of the compound ingredient may also be problematic. For example, some of the conventional dispersions described above, particularly those prepared using organic solvents, must be processed by milling to obtain the fine particles required for final product (e.g., tabletting or capsule filling). Milling or similar size reduction processes, however, provides irregularly shaped particles that are polydisperse, which may contribute to variability in dissolution rates. Conventional formulations that require processing at highly elevated temperatures may also require extended cooling times. In addition, other special processing may be required when handling these formulations to minimize recrystallization of the compound within the carrier matrix. Problems may also arise during the dissolution of compound from dosage forms prepared using such conventional formulation technology. Generally, the carriers used to prepare the solid dispersions, such as high molecular weight (MW>3000) polyethylene glycols (PEGs), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), and the like, possess better water solubility characteristics than the compounds dispersed therein. As the carriers preferentially dissolve, tiny amounts of the slowly dissolving compound are left on the surface of the solid particles. If the rate of dissolution of the carrier is much greater than the rate of compound dissolution, agglomeration or crystallization of the compound may occur, thereby reducing its dissolution in the gastrointestinal (GI) media which may result in reduced bioavailability. In addition, these carriers does not have the ability to emulsify precipitated particles which can also adversely affect the dissolution and bioavailability of the compound.
Accordingly, it would be desirable to provide a formulation for compounds, particularly sparingly soluble compounds, that would provide enhanced bioavailability characteristics, that can be processed into a variety of final physical forms, and that can be prepared using mild formulation conditions, without the need for using organic solvents and without the need to heat the compound to temperatures above its melting point.